ATP-citratelyase (ACL) is an extramitochondrial enzyme that is expressed in lipogenic tissues such as liver and adipose. And it’s responsible for the production of cytosolic acetyl-CoA, a precursor required for de novo biosyntheses of cholesterol and fatty acids. BMS-303141 is an ACL inhibitor displaying potent in vitro activity (IC50 = 0.13 μM). And it showed inhibition of total lipid syntheses with an IC50 of 8 μM in HepG2 cells. In mice, BMS-303141 showed an oral bioavailability of 55% and a half-life of 2.1 hr. Two high-fat diet mice groups were supplemented with BMS-303141 to an equivalent daily dose of 10 or100 mg/kg for 34 days. There was a modest lowering of both plasma cholesterol and triglycerides after 20 days of treatment. A reduction in fasting plasma glucose was observed from day 7 to completion of the study. At day 29, cholesterol was lowered by 19% with the 100 mg/kg dose and triglycerides were lowered by 26% in both the 10 and 100 mg/kg treatment groups. Fasting plasma glucose was lowered by 48% and 32% for 10 and100 mg/kg doses, respectively[3].
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